Cellular senescence in progeroid syndromes

The relationship between progerias (syndromes that mimic multiple aspects of aging) and aging per se remains controversial: some conditions are best thought of “segmental” progerias (in that they model aging only in specific organs or cell types), whereas others model the natural aging process very closely in the majority of tissues. Chief among the latter are Werner’s Syndrome (WS) and Hutchinson-Gilford Progeria Syndrome (HGPS).

The underlying mutation in the two diseases are quite different: WS is due to a mutation in a DNA helicase involved in repair, whereas HGPS is caused by a dominant mutation in lamin A/C, a which is critical to nuclear structure (and consequently in gene regulation). While the diseases have distinct phenotypes and ages of onset, they are both widely considered good models of accelerated aging. What, if anything, is the common currency beteween the two?

In a recent review article, Cox and Faragher argue that premature cellular senescence is likely to be important in both WS and HGPS:

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner’s syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner’s syndrome and Hutchinson-Gilford progeriod syndrome.

The idea that cellular senescence is important in normal aging happens to be favored in my current lab, and increasingly seems to be the mainstream position (see especially Devil’s bargain: Tradeoffs between stem cell maintenance and tumor suppression, and also here and here). According to this model, senescence (which permanently growth-arrests old and damaged cells) prevents individual cells from forming tumors, but persistent senescent cells embark on a highly anti-social program of gene expression that can surrounding tissues and may contribute to age-related decline in tissue function. Many experiments remain to be done before we can claim confidently that senescence plays a causative role in aging; for now, the most I can say is that the existing data are consistent with the idea.

Advertisements

Share this:

Like this:

Related

2 Responses to “Cellular senescence in progeroid syndromes”

This brings me to a question I’ve been stumped on since I started (potentially) seeing it in some of my work, and then similar-ish results were published from Scott Lowe’s lab (Xue et al. Nature 2007):
The removal/clearance of senescent cells.
I had thought senescent cells “permanently growth-arrests old and damaged cells” subsequently residing in a tissue leading to it’s malfunction with age.
But Lowe’s data showed that the senescence-tumor response (at least in liver) cells were cleared by the innate immune system.
So what is the cellular difference between an old cell becoming senescent and remaining, and a tumor cell becoming senescent and then cleared?
Maybe defects in immune responses with age? If so, would a key to rejuvenation just be kick starting immunity?
I’m sure I’m short cutting a lot of systems.
thoughts?
comments?
I’d really appreciate a brainstorm!

I think this issue can be resolved fairly simply: All senescent cells are targeted for clearance, but the clearance is not performed with 100% efficiency, so some do persist.

There are certainly age-related changes in the immune system that could make clearance less efficient as time goes by, which would result in senescent cells accumulating at an exponential rather than linear rate.

I can’t say a lot more about this in this forum, but our lab has a paper coming out about the issue of clearance sometime later this year, which will go a long way toward resolving some of the apparent paradoxes between the Lowe lab’s observation and the theory that senescent cells contribute to age-related decline in tissue function.